Carbothioamide functionalized paroxetine analogues as antiparasitic agents targeting the hypoxanthine-guanine-xanthine phosphoribosyltransferase enzyme: Synthesis, characterization, biochemical, biophysical, and in silico studies
4 affiliations
- 1Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
- 2H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
- 3Institute of Molecular Biology and Biochemistry, The University of Lahore, LahorePakistan.
- 4Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang, China.
Abstract
Hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) is one of the central enzymes of purine salvage pathway of protozoan parasites, including Plasmodium. These parasites are purine auxotrophs, and rely on purine salvage pathway for nucleic acid synthesis. Inhibiting the enzymatic activity can effectively reduce the parasite- induced infections, including malaria. In this context, a library of new carbothioamide derivatives 1–17 of paroxetine was synthesized via single-step chemical transformation strategy with a series of substituted phenyl isothiocyanates. All compounds were purified, and their structures were deduced by using spectroscopic techniques, such as mass, FT-IR, UV, and 1H-, and 13C-NMR. These compounds were evaluated for their HGXPRT inhibitory activity via in vitro UV-based spectrophotometric assay. All derivatives 1–17 showed varying potential to inhibit the enzyme activity with IC50 values between 19.0 to 76.9 µM, with highest activity showed by compound 13 (IC50 = 19.0 ± 2.09 µM) within the series, but remained less potent than the standard (9-deazaguanine, IC50 = 12.00 ± 1.0 µM). Biophysical, molecular docking, and molecular simulation studies were carried out further to analyse the enzyme-inhibitor interaction, and stability. These compounds were predicted to occupy the putative allosteric site of enzyme. Furthermore, cytotoxic profile of these compounds were also evaluated via ADMET analysis and MTT assay, and found to be largely non-cytotoxic. The current study has identified potential hits against HGXPRT enzyme that could further be investigated as anti-parasitic drugs.
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BibTeX
@article{hammal2026carbothioamide,
title = {{Carbothioamide functionalized paroxetine analogues as antiparasitic agents targeting the hypoxanthine-guanine-xanthine phosphoribosyltransferase enzyme: Synthesis, characterization, biochemical, biophysical, and in silico studies}},
author = {Laleen Hammal and Mukhtiyar Ali and Naveera Zafar and Saima Hassan Mari and Humaira Zafar and Atia-Tul- Wahab and Hina Siddiqui and Sumaira Javaid and Muhammad Iqbal Choudhary},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0359519},
url = {https://doi.org/10.1371/journal.pone.0359519},
note = {CC BY},
}
RIS
TY - JOUR
TI - Carbothioamide functionalized paroxetine analogues as antiparasitic agents targeting the hypoxanthine-guanine-xanthine phosphoribosyltransferase enzyme: Synthesis, characterization, biochemical, biophysical, and in silico studies
AU - Laleen Hammal
AU - Mukhtiyar Ali
AU - Naveera Zafar
AU - Saima Hassan Mari
AU - Humaira Zafar
AU - Atia-Tul- Wahab
AU - Hina Siddiqui
AU - Sumaira Javaid
AU - Muhammad Iqbal Choudhary
PY - 2026
DA - 2026/10/22
JO - PLOS One
DO - 10.1371/journal.pone.0359519
UR - https://doi.org/10.1371/journal.pone.0359519
AB - Hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT) is one of the central enzymes of purine salvage pathway of protozoan parasites, including Plasmodium. These parasites are purine auxotrophs, and rely on purine salvage pathway for nucleic acid synthesis. Inhibiting the enzymatic activity can effectively reduce the parasite- induced infections, including malaria. In this context, a library of new carbothioamide derivatives 1–17 of paroxetine was synthesized via single-step chemical transformation strategy with a series of substituted phenyl isothiocyanates. All compounds were purified, and their structures were deduced by using spectroscopic techniques, such as mass, FT-IR, UV, and 1H-, and 13C-NMR. These compounds were evaluated for their HGXPRT inhibitory activity via in vitro UV-based spectrophotometric assay. All derivatives 1–17 showed varying potential to inhibit the enzyme activity with IC50 values between 19.0 to 76.9 µM, with highest activity showed by compound 13 (IC50 = 19.0 ± 2.09 µM) within the series, but remained less potent than the standard (9-deazaguanine, IC50 = 12.00 ± 1.0 µM). Biophysical, molecular docking, and molecular simulation studies were carried out further to analyse the enzyme-inhibitor interaction, and stability. These compounds were predicted to occupy the putative allosteric site of enzyme. Furthermore, cytotoxic profile of these compounds were also evaluated via ADMET analysis and MTT assay, and found to be largely non-cytotoxic. The current study has identified potential hits against HGXPRT enzyme that could further be investigated as anti-parasitic drugs.
SN - 1932-6203
ER -